46,XY sex reversal 2

Summary

46,XY sex reversal 2 (MONDO:0010226) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 290

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY sex reversal 2
Mondo ID	MONDO:0010226
MeSH	C535601
OMIM	300018
DOID	DOID:0111777
UMLS	C1848296
MedGen	341190
GARD	0009159
Is cancer (heuristic)	no

Also known as: 46,XY sex reversal 2 · 46,XY Sex reversal type 2 · SRXY2

Data availability: 290 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46,XY complete gonadal dysgenesis › 46,XY sex reversal 2

Related subtypes (11): 46,XY sex reversal 4, 46,XY sex reversal 7, 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, 46,XY sex reversal 3, 46,XY sex reversal 5, 46,XY sex reversal 6, 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency, 46,XY sex reversal 9, 46,XY sex reversal 10, 46,XY sex reversal 1, 46,XY sex reversal 11

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

290 retrieved; paginated sample, class counts are floors:

139 likely benign, 64 uncertain significance, 36 pathogenic, 26 benign, 14 conflicting classifications of pathogenicity, 6 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2423143	NC_000023.10:g.(?28807461)(33229429_?)dup	DMD	Pathogenic	criteria provided, single submitter
1075657	NM_000475.5(NR0B1):c.226C>T (p.Gln76Ter)	NR0B1	Pathogenic	criteria provided, single submitter
10952	NM_000475.5(NR0B1):c.800G>C (p.Arg267Pro)	NR0B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10962	NC_000023.11:g.(?30304206_30309390?)dup	NR0B1	Pathogenic	no assertion criteria provided
10967	NM_000475.5(NR0B1):c.1231_1234del (p.Leu411fs)	NR0B1	Pathogenic	criteria provided, single submitter
10970	NM_000475.5(NR0B1):c.501del (p.Gly169fs)	NR0B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1371683	NM_000475.5(NR0B1):c.1168+1del	NR0B1	Pathogenic	criteria provided, single submitter
2014691	NM_000475.5(NR0B1):c.1286_1295del (p.Leu429fs)	NR0B1	Pathogenic	criteria provided, single submitter
2020326	NM_000475.5(NR0B1):c.405T>A (p.Cys135Ter)	NR0B1	Pathogenic	criteria provided, single submitter
2115793	NM_000475.5(NR0B1):c.382_425dup (p.Gln142fs)	NR0B1	Pathogenic	criteria provided, single submitter
2134496	NM_000475.5(NR0B1):c.271del (p.Tyr91fs)	NR0B1	Pathogenic	criteria provided, single submitter
2138497	NM_000475.5(NR0B1):c.1292del (p.Ser431fs)	NR0B1	Pathogenic	criteria provided, single submitter
2138500	NM_000475.5(NR0B1):c.292G>T (p.Glu98Ter)	NR0B1	Pathogenic	criteria provided, single submitter
2423142	NC_000023.10:g.(?30322696)(30327480_?)del	NR0B1	Pathogenic	criteria provided, single submitter
2921342	NM_000475.5(NR0B1):c.25C>T (p.Gln9Ter)	NR0B1	Pathogenic	criteria provided, single submitter
2925663	NM_000475.5(NR0B1):c.664C>T (p.Gln222Ter)	NR0B1	Pathogenic	criteria provided, single submitter
2940031	NM_000475.5(NR0B1):c.509_510dup (p.Trp171fs)	NR0B1	Pathogenic	criteria provided, single submitter
2941501	NM_000475.5(NR0B1):c.1104C>A (p.Cys368Ter)	NR0B1	Pathogenic	criteria provided, single submitter
2951215	NM_000475.5(NR0B1):c.418_452del (p.His139_Pro140insTer)	NR0B1	Pathogenic	criteria provided, single submitter
3243899	NC_000023.10:g.(?30322696)(30327480_?)dup	NR0B1	Pathogenic	criteria provided, single submitter
3383055	NM_000475.5(NR0B1):c.564_567dup (p.Gly190fs)	NR0B1	Pathogenic	criteria provided, single submitter
3755336	NM_000475.5(NR0B1):c.603_604del (p.Phe201fs)	NR0B1	Pathogenic	criteria provided, single submitter
3757778	NM_000475.5(NR0B1):c.1037_1038insA (p.Ala347fs)	NR0B1	Pathogenic	criteria provided, single submitter
3757817	NM_000475.5(NR0B1):c.1099_1100insT (p.Lys367fs)	NR0B1	Pathogenic	criteria provided, single submitter
3759749	NM_000475.5(NR0B1):c.184dup (p.Leu62fs)	NR0B1	Pathogenic	criteria provided, single submitter
429744	NM_000475.5(NR0B1):c.708G>A (p.Trp236Ter)	NR0B1	Pathogenic	criteria provided, multiple submitters, no conflicts
444090	NM_000475.5(NR0B1):c.327C>A (p.Cys109Ter)	NR0B1	Pathogenic	criteria provided, multiple submitters, no conflicts
460310	NM_000475.5(NR0B1):c.516G>A (p.Trp172Ter)	NR0B1	Pathogenic	criteria provided, multiple submitters, no conflicts
460311	NM_000475.5(NR0B1):c.552del (p.Glu185fs)	NR0B1	Pathogenic	criteria provided, single submitter
460312	NM_000475.5(NR0B1):c.901C>T (p.Gln301Ter)	NR0B1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NR0B1	Moderate	X-linked	46,XY sex reversal 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR0B1	Orphanet:242	46,XY complete gonadal dysgenesis
NR0B1	Orphanet:251510	46,XY partial gonadal dysgenesis
NR0B1	Orphanet:393	46,XX testicular difference of sex development
NR0B1	Orphanet:95702	X-linked adrenal hypoplasia congenita
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR0B1	HGNC:7960	ENSG00000169297	P51843	Nuclear receptor subfamily 0 group B member 1	gencc,clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR0B1	Nuclear receptor subfamily 0 group B member 1	Nuclear receptor that lacks a DNA-binding domain and acts as a corepressor that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	192.9×	0.010
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR0B1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Nuclear_hrmn_rcpt, Nuclear_receptor_repeat
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
left adrenal gland	1
right adrenal gland	1
dorsal root ganglion	1
skeletal muscle tissue of rectus abdominis	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR0B1	130	broad	marker	right adrenal gland, left adrenal gland, adrenal tissue
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DMD	2,479
NR0B1	1,753

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DMD	P11532	6
NR0B1	P51843	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	1	154.3×	0.013	DMD
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.013	DMD
Nuclear Receptor transcription pathway	1	100.2×	0.013	NR0B1
Non-integrin membrane-ECM interactions	1	77.2×	0.013	DMD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of muscle system process	1	8426.0×	0.002	DMD
regulation of cellular response to growth factor stimulus	1	8426.0×	0.002	DMD
intracellular protein localization	2	104.7×	0.002	NR0B1, DMD
cardiac muscle cell action potential	1	4213.0×	0.002	DMD
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	2106.5×	0.003	DMD
negative regulation of intracellular steroid hormone receptor signaling pathway	1	2106.5×	0.003	NR0B1
peptide biosynthetic process	1	2106.5×	0.003	DMD
negative regulation of steroid biosynthetic process	1	1685.2×	0.003	NR0B1
regulation of skeletal muscle contraction	1	1404.3×	0.003	DMD
regulation of calcium ion transmembrane transport	1	1053.2×	0.004	DMD
sex determination	1	842.6×	0.004	NR0B1
Sertoli cell differentiation	1	766.0×	0.004	NR0B1
synaptic signaling	1	766.0×	0.004	DMD
male sex determination	1	702.2×	0.004	NR0B1
Leydig cell differentiation	1	601.9×	0.004	NR0B1
gonad development	1	561.7×	0.004	NR0B1
hypothalamus development	1	526.6×	0.004	NR0B1
regulation of sodium ion transmembrane transport	1	526.6×	0.004	DMD
muscle cell development	1	468.1×	0.005	DMD
negative regulation of gluconeogenesis	1	401.2×	0.005	NR0B1
response to muscle stretch	1	383.0×	0.005	DMD
response to immobilization stress	1	366.4×	0.005	NR0B1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.005	DMD
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	337.0×	0.005	DMD
adrenal gland development	1	337.0×	0.005	NR0B1
pituitary gland development	1	324.1×	0.005	NR0B1
muscle cell cellular homeostasis	1	324.1×	0.005	DMD
motile cilium assembly	1	290.6×	0.005	DMD
endodermal cell differentiation	1	247.8×	0.006	NR0B1
maintenance of blood-brain barrier	1	240.7×	0.006	DMD

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NR0B1	PODOFILOX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR0B1	3	4
DMD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PODOFILOX	4	NR0B1
VORINOSTAT	4	NR0B1
COLFORSIN	2	NR0B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NR0B1	3	Functional:2, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PODOFILOX	4	NR0B1
VORINOSTAT	4	NR0B1
COLFORSIN	2	NR0B1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NR0B1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DMD

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DMD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.